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One of the earliest and most important articles relating to SBMA was written by Dr. William R. Kennedy, after whom the disease is named. Another seminal article in SBMA research was authored by Dr. Kenneth H. Fischbeck, who identified the genetic trait which causes SBMA. Dr. Fischbeck is one of the leading neurogenetic researchers in the world today.
Kennedy, W.R., Alter, M., Sung, J.H., Progressive proximal spinal
and bulbar muscular atrophy of late onset: a sex-linked recessive
trait. Neurology 18: 671-680, 1968.
Fischbeck, et al., Localization of the gene for X-linked spinal
muscular atrophy. Neurology 36: 1595-1598, 1986.
These abstracts are from a PubMed NIH MEDLINE query. To read the original, visit your local university or hospital library. To obtain a copy of an article, you may visit the NIH, PubMed, or Grateful Med internet sites where you can order a copy online. These articles are generally arranged by publication date. Use your browser's find command to go to the subjects, authors, or dates in which you have interest.
Mech Dev 1998 Mar;72(1-2):175-178
Forschungszentrum Karlsruhe, Institute of Genetics, P.O. Box 3640, D-76021, Karlsruhe, Germany.
[Medline record in process]
Androgen receptor (AR) is a member of the nuclear receptor superfamily which acts as a ligand-dependent transcription factor (Beato, M., Herrlich, P., Schutz, 1989. Steroid hormone receptors: many actors in search of a plot. Cell 83, 851-857). It plays a pivotal role in sexual development and reproduction (Wilson, J.D., Griffin, J.E., George, F.W., Leshin, M., 1981. The role of gonadal steroids in sexual differentiation. Rec. Prog. Horm. Res. 37, 1-39; Jost, A., 1990. Hormonal control of the masculinization of the body. In: Baulieu, E.E., Kelly, D.A., (Eds.), Hormones, from Molecules to Disease. Chapman and Hall, New York and London, pp. 439-442.). Mutations in the AR sequence cause a number of physiological disorders, such as partial and complete androgen insensitivity syndromes, that lead to abnormal sexual development (Patterson, M.N., McPhaul, M.J., Hughes, I.A., 1994. Androgen insensitivity syndrome. Balliere's Clin. Endocrinol. Metab. 8, 379-404.). There are indications that AR may also have other functions. For example, structural alterations of the AR sequence have been implicated in prostate cancer (Visakorpi, T., Huytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., Palotie, A., Tammela, T., Isola, J., Kallioniemi, O.-P., 1995. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet. 9, 401-406.) and in the development of spinal and bulbar muscular atrophy, a neurodegenerative disease (Kennedy, W.R., Alter, M., Sung, J.H., 1968. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 18, 671-680.). Here, we have investigated the spatial and temporal expression of AR during mouse organogenesis by in situ hybridisation. We demonstrate that AR transcripts occur in the developing external genitalia, pituitary, adrenals, kidneys and musculus levator ani, in addition to the known expression sites in the Wolffian ducts and its derivatives and during development of the mammary glands. Copyright 1998 Elsevier Science Ireland Ltd.
PMID: 9533962, UI: 98202523
Hum Mol Genet 1998 Jan;7(1):121-127
Department of Clinical Neurosciences, Institute of Psychiatry and King's College School of Medicine and Dentistry, De Crespigny Park, London SE5 8AF, UK.
X-linked spinal and bulbar muscular atrophy (SBMA) is a rare form of motor neuron degeneration linked to a CAG repeat expansion in the first exon of the androgen receptor gene coding for a polyglutamine tract. In order to investigate the properties of the SBMA androgen receptor in neuronal cells, cDNAs coding for a wild-type (19 CAG repeats) and a SBMA mutant androgen receptor (52 CAG repeats) were transfected into mouse neuroblastoma NB2a/d1 cells. The full length androgen receptor proteins, of 110-112 kDa and 114-116 kDa for the wild-type and mutant protein, respectively, were detected by Western blotting in transfected cells. In addition, the presence of an expanded polyglutamine tract in the SBMA androgen receptor appears to enhance the production of C-terminally truncated fragments of the protein. A 74 kDa fragment was particularly prominent in cells expressing the SBMA androgen receptor. From its size, it can be deduced that the 74 kDa fragment lacks the hormone binding domain but retains the DNA binding domain. The 74 kDa fragment may therefore be toxic to motor neurons by initiating the transcription of specific genes in the absence of hormonal control. Immunofluorescence microscopy on transfected NB2a/d1 cells showed that, after hormone activation, the wild-type androgen receptor translocated to the nucleus whereas the SBMA androgen receptor was mainly localized in the cytoplasm in the form of dense aggregates with very little androgen receptor protein in the nucleus. This could explain the reduction in transcriptional activity of the SBMA mutant as compared with wild-type androgen receptor.
Grant support:
PMID: 9384612, UI: 98046015
J Inherit Metab Dis 1997 Jun;20(2):152-158
Department of Neurology, University of Pennsylvania Medical School, Philadelphia 19104, USA.
Kennedy disease is a disorder with progressive motor neuron degeneration that is caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism likely involves toxicity of an expanded polyglutamine tract in the androgen receptor protein. This mechanism is probably shared by other neurodegenerative disorders with polyglutamine expansion, including Huntington disease. Attempts at reproducing the Kennedy disease phenotype by introducing the expanded androgen receptor into cultured neuronal cells and transgenic animals have thus far been unsuccessful, but recently developed model systems with other expanded polyglutamine constructs should allow the pathogenesis of these diseases to be elucidated.
Grant support:
PMID: 9211187, UI: 97354992
Hum Genet 1997 Jun;99(6):701-703
Department of Neurology, Northwestern University Medical School, Chicago, IL 60611-3008, USA.
Scapuloperoneal spinal muscular atrophy (SPSMA) is a neuromuscular disorder characterized by weakness in the distribution of shoulder girdle and peroneal muscles. We have previously described a large New England kindred with autosomal dominant SPSMA and have subsequently linked this family trait to 12q24.1-q24.31. In this family, disease expression becomes more severe and progressive in successive generations, suggesting genetic anticipation. Accordingly, we have investigated the thirteen known CAG/CTG repeat loci on chromosome 12 that could be tested by using the polymerase chain reaction as candidate genetic mutations in SPSMA. None of these loci is expanded.
PMID: 9187660, UI: 97331328
Muscle Nerve 1997 Mar;20(3):323-329
Neurology Department, Keesler Medical Center, Keesler Air Force Base, Mississippi, USA.
To define the electrodiagnostic (EDX) features of Kennedy's disease, their distribution, their clinical correlation, and to determine whether they are unique to this disorder, we retrospectively evaluated the EDX and clinical features of 19 patients with Kennedy's disease and found that: (1) the percentage with sensory nerve action potential abnormalities is high (95%); (2) compound muscle action potential abnormalities are less frequent (37%) and less pronounced; (3) the needle electrode examination is always abnormal (100%), revealing acute and chronic motor axon loss, with the latter predominating; (4) the clinical onset is heterogeneous for both the site of onset (bulbar, upper extremity, lower extremity, combination) and the symptomatology (sensory, motor, sensorimotor); (5) focal onsets were reported in the majority (79%); and (6) there is a strong correlation between the clinical onset (both site and symptomatology) and the maximal EDX abnormalities. Thus, the EDX features of Kennedy's disease are consistent with a slowly progressive and very chronic degeneration of the anterior horn cells and dorsal root ganglia. Although the clinical onsets are heterogenous, the EDX features are homogenous and unique, consisting of a diffuse, very slowly progressive anterior horn cell disorder coupled with a sensory neuropathy/neuronopathy that mimics an acquired process.
PMID: 9052811, UI: 97205307
Am J Med Genet 1997 Mar 17;69(2):159-165
Department of Genetics, Children's Hospital of Eastern Ontario, Canada.
The molecular genetic diagnosis of spinal muscular atrophy (SMA) has recently been complicated by the identification of two candidate genes, which are often deleted in affected individuals but are also occasionally deleted in apparently unaffected carriers. We present a compilation of genotypes, from our laboratory and recent reports, for the survival motor neuron (SMN) and neuronal apoptosis inhibitor protein (NAIP) genes. Bayesian analyses were used to generate probabilities for SMA when deletions are present or absent in SMN. We found that when the SMN(T) exon 7 is deleted, the probability of SMA can reach greater than 98% in some populations, and when SMN(T) is present, the probability of SMA is approximately 17 times less than the prior population risk. Deletion of NAIP exon 5, as well as SMN(T) exon 7, is associated with a 5-fold increased risk of type I SMA. Case studies are used to illustrate differing disease risks for pre- and postnatal testing, depending on the presence of information about clinical status or molecular results. These analyses demonstrate that deletion screening of candidate genes can be a powerful tool in the diagnosis of SMA.
PMID: 9056553, UI: 97209253
J Neurol Sci 1997 Mar 10;146(2):183-185
Department of Neurology, Faculty of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Japan.
We describe a patient with X-linked spinal and bulbar muscular atrophy (X-SBMA) and myasthenic symptoms. The diagnosis of X-SBMA was established by demonstration of the increased number of CAG repeats in the androgen receptor gene on the X chromosome. This patient was characterized by the clinical symptoms of fatigability, decremental motor responses to repetitive nerve stimulation, and improvement of the myasthenic symptoms with oral administration of pyridostigmine. No serum antibody to acetylcholine receptor was detected. It is suggested that, in the process of chronic denervation and reinnervation of X-SBMA, reinnervated motor endplates may be associated with the defect of neuromuscular transmission.
PMID: 9077516, UI: 97232241
Neurology 1997 Jan;48(1):23-28
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Axonal forms of autosomal dominant hereditary motor and sensory neuropathies (HMSNs) represent a heterogeneous group of disorders based on genetic linkage studies. We recently identified one large family with axonal HMSN exhibiting linkage to chromosome 3q, designated HMSN IIB, and report here the clinical and electrodiagnostic features. We clinically evaluated 10 individuals with HMSN IIB and performed detailed electrophysiologic studies in 5 of these patients. HMSN IIB is characterized clinically by the presence of distal symmetric motor weakness and prominent sensory loss affecting the lower extremities with preserved ankle reflexes. Symptomatic age at onset is in the second or early third decade of life. Six patients with HMSN IIB had distal trophic ulcerations in the feet, leading to eventual toe amputations in four cases. Electrodiagnostic studies confirmed a distal sensorimotor axonopathy involving the lower limbs with normal motor conduction velocities. Tibial H-reflexes were preserved in HMSN IIB, despite the uniform loss of sural nerve potentials. Overall, individuals with HMSN IIB demonstrated a consistent clinical and electrodiagnostic phenotype that had no overlap with genetically unaffected family members. The identification of specific clinical and electrodiagnostic features of HMSN IIB may prove useful in the diagnosis and differentiation between various subtypes of HMSN II.
PMID: 9008488, UI: 97161231
J Med Genet 1997 Jan;34(1):86-87
Publication Types:
PMID: 9032657, UI: 97184888
Horm Res 1997;47(1):23-29
Unite BEDR, Hopital Lapeyronie, Montpellier, France.
We have performed a molecular analysis of the androgen receptor gene in two families with suspected Kennedy's disease (spinal and bulbar muscular atrophy, SBMA) with the aim of making a firm diagnosis of the disease. The 2 patients studied were sporadic cases. Both presented clinical signs compatible with the diagnosis of SBMA: limb and facial muscular weakness of adult onset progressing toward muscular atrophy. Clinical signs of partial androgen insensitivity syndrome usually observed in SBMA were present only in patient 2. Enzymatic amplification of the CAG repeat region of exon 1 of the androgen receptor gene was performed on genomic DNA. PCR products were submitted to agarose or acrylamide electrophoresis for size evaluation. Precise determination of the CAG number was performed by direct sequencing of purified amplification products. Androgen receptor gene analysis was also performed in 2 sisters of patient 1 and in the mother, sisters and daughter of patient 2. Androgen receptor-binding activity was also determined on cultured genital skin fibroblasts of patient 1. Analysis of PCR products showed in both patients a single band that was much larger in size than the control. The expansion of the CAG repeat number was confirmed by direct sequencing: the exact number of CAG was 47 in patient 1 and 42 in patient 2 (n = 12-32). The 2 studied sisters of patient 1 did not present the abnormal fragment, demonstrating they are not carriers for the disease. Conversely, the mother, sisters and daughter of patient 2 presented both normal and mutated alleles. The migration of the labelled PCR products on a sequencing gel revealed a meiotic instability of expanded CAG repeat in family 2. Moreover, patient 1 had a decreased androgen-binding capacity on cultured genital skin fibroblasts. In both families, analysis of the androgen receptor gene permitted us to diagnose SBMA in the patients and to establish the carrier status in siblings. These results correspond to the literature data and confirm the usefulness of CAG repeat evaluation in the diagnosis of Kennedy's disease. They highlight the relationship between the androgen receptor and motoneuron growth, development and regeneration.
PMID: 9010714, UI: 97163967
Zh Nevropatol Psikhiatr Im S S Korsakova 1997;97(3):45-48
[Article in Russian]
Seven relatives of previously described proband with X-linked Kennedy's spinal and bulbar muscular atrophy (SBMA) were investigated by means of clinical, biochemical and molecular genetic methods. The patients' age was 13-70 years. Clinical and biochemical investigations revealed SBMA in two males. Molecular genetic analysis by means of polymerase chain reaction (PCR) revealed pathological expansion of trinucleotide CAG repetitions in 5'-region of androgene receptor gene in both patients. Five heterozygous female carriers were discovered meanwhile. PCR-method permitted to diagnose the disease exactly, to reveal heterozygous carrier of pathological gene and to perform potential prenatal diagnosis.
PMID: 9157759, UI: 97251792
Neurologia 1996 Dec;11 Suppl 5:14-19
[Article in Spanish]
Unitat de Genetica Molecular, Hospital de la Santa Creu i Sant Pau, Barcelona.
Spinal muscular atrophies constitute a group of hereditary diseases characterized by degeneration of the anterior horn of the spinal cord. Molecular studies began in 1990 with the location of the genome region responsible for the disease in chromosome 5q13. New directions for research were opened in 1995 with the identification of the affected region in the survival motor neuron (SMN) genes and the neuronal apoptosis inhibitory protein genes. A main feature of these genes is that they are duplicate, forming part of two elements (centromeric and telomeric) that include mini-satellites that are also repeated, making this zone particularly unstable. The molecular abnormalities found in patients are a consequence of that instability: gene deletions and conversions in the SMN gene have been described independently of whether symptoms were severe or not. Molecular data make it possible to confirm the clinical diagnosis of most patients and to provide certain prenatal diagnosis for couples that are at high risk of passing on the disorder. Determining both the function of these genes and their pathogenesic role will help to ground new therapeutic strategies that will prevent or detain motor neuron degeneration.
PMID: 9044570, UI: 97164500
Mol Endocrinol 1996 Dec;10(12):1527-1535
Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill 27599-7500, USA.
The molecular basis for partial androgen insensitivity associated with adult onset spinal/bulbar muscular atrophy was investigated by transient transfection of human androgen receptor (AR) expression vectors containing increasing CAG repeat lengths in the first exon. An inverse relationship was observed between CAG repeat length and AR mRNA and protein levels. Trinucleotide repeat lengths of 43 and 65 associated with spinal/bulbar muscular atrophy decreased AR mRNA and protein levels but did not alter equilibrium binding affinity for [3H]R1881 or inherent transcriptional activity of AR, expressed as androgen-dependent fold induction of a mouse mammary tumor virus promoter-luciferase reporter vector. The findings indicate that glutamine expansion up to 66 residues in the NH2-terminal domain of AR does not alter AR functional activity. Rather, CAG repeat expansion in the region of the first exon reduces AR mRNA and protein expression. The study reveals a previously unrecognized effect of CAG repeat length on AR mRNA expression and a novel molecular mechanism for androgen resistance.
Grant support:
PMID: 8961263, UI: 97120592
Neurologia 1996 Dec;11 Suppl 5:20-28
[Article in Spanish]
Servicio de Neurofisiologia Clinica, Hospital del Mar, Universidad Autonoma de Barcelona.
Electrophysiologic assessment is an important diagnostic tool in motor neuron diseases, contributing on occasions to define a patient's prognosis and clinical course as well as to further our understanding of the disease itself. The advent of motor cortex stimulation techniques facilitates the study of impaired descending motor pathways in predominantly upper motor neuron forms of amyotrophic lateral sclerosis. The most important feature of this technique is the decrease in amplitude of muscle responses to cortical stimuli, as a reflection of upper and lower motor neuron death. Coaxial needle electromyography (EMG) affords data on muscle fiber denervation as well as alterations in motor unit potentials, whose amplitude and duration increase. Motor and sensory nerve conduction velocities are preserved: single fiber and macro-EMG studies reveal changes suggestive of collateral sprouting of distal axons in surviving motor units in a compensatory reinnervation process. None of these techniques, however, provides a direct measure of the number of motor units present in a muscle, information that would be an essential aid in following the natural course of such diseases as well as assessing the efficacy of experimental treatments. Several techniques for estimating the number of motor units have been put forth, although none has been widely accepted. We describe the techniques proposed, weighing the advantages and disadvantages of each. At present it is impossible to tell which technique best estimates the real number of motor units present.
PMID: 9044571, UI: 97164501
Med Assoc Thai 1996 Dec;79 Suppl 1:S11-S14
Department of Anatomy, Chulalongkorn University, Bangkok, Thailand.
PMID: 9071062, UI: 97224678
Neurologia 1996 Dec;11 Suppl 5:43-57
[Article in Spanish]
Servei de Neurologia, Hospital del Mar, Universitat Autonoma de Barcelona.
We propose a classification system for spinal muscular atrophies (SMA) based on the distribution of clinical signs, paresis and atrophy, as well as on the location of the responsible gene and the resulting enzyme deficiency, whenever these are known. This highly practical classification system encompasses three large SMA groups, as follows. A) Generalized forms, many of which are hereditary, are generally transmitted in a recessive autosomal manner. The course of disease is more severe when symptoms manifest early. Patients whose symptoms first occur after the first year of life often reach adolescence and even adulthood, confirming a highly apparent congruence of intermediate and pseudomyopathic juvenile forms. The same genetic defect, deletion in the 5q11-13.3 locus, that is responsible for acute infantile SMA has been demonstrated in both the aforementioned forms. B) Focal forms are restricted and often isolated cases; when they are hereditary, the genetic profile is highly heterogeneous. Though the disease will not necessarily evolve, it may progress to a generalized form. Focal forms may be symetric, assymetric, spinal-bulbar or multisegmental. The genetic abnormality has been identified for only some forms, such as chronic bulbar-spinal amyotrophy linked to the X-chromosome, at whose location, Xq11, the androgenic receptor is found. C) Amyotrophic lateral sclerosis (ALS) manifests clinically in a variety of ways and may be isolated, familial, juvenile or associated. Familial ALS is related to a gene defect in the 21q22.1 location that codifies for the superoxide dismutase enzyme. One juvenile form of ALS is related to a defect in the 2q33-35 chromosome. Any type of SMA can be related to degenerative neuronal disease of the central nervous system, especially juvenile ALS with generalized SMA, although such a link is at present merely an attractive hypothesis. Specific bibliographic references are given for each SMA form. Figures are provided to illustrate most of the SMA forms included in this classification system, the patients being at this time older adolescents and adults whose disease has been in evidence over many years.
PMID: 9044573, UI: 97164503
FASEB J 1996 Dec;10(14):1589-1597
Department of Medicine, Section of Cardiology, Baylor College of Medicine, Houston, Texas 77030, USA.
Several human disorders are now known to be caused by expansion of unstable trinucleotide repeat sequences, including fragile X syndrome (FRAX), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy disease), Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD), and Friedreich ataxia. As these diseases are studied in more detail, important differences have emerged in the nature of the unstable repeats and the mechanism by which the repeat expansions cause disease symptoms. There are already animal models of some of these disorders, and these are important resources for studying pathology and therapeutic strategies. Diagnostic procedures for these disorders are only beginning to be standardized, and effective therapy will have to wait for further information on disease mechanisms. Much has been learned since discovery of the fragile X syndrome gene in 1991, but much remains to be done.
Grant support:
PMID: 9002550, UI: 97156073
Hokkaido Igaku Zasshi 1996 Nov;71(6):785-799
[Article in Japanese]
Department of Neurology, Hokkaido University, School of Medicine, Sapporo, Japan.
X-linked spinal and bulbar muscular atrophy (SBMA), a rare adult onset form of motor neuron disease, is clinically characterized by slowly progressive muscle weakness and atrophy, and endocrinopathy such as gynecomastia, testicular atrophy and oligospermia. Androgens are known to play an important role in motor neuron growth, development and regeneration. The genetic mutation of androgen receptor (AR) gene in SBMA has been disclosed and thought to lead to degeneration of lower motor neurons. However, the mechanism of neuronal death and the basis for the regional specificity of neuropathology observed in SBMA are not clear. At first, we proved the existence of androgen receptor (AR) in the motor neurons of the rat spinal cord by the immunohistochemical stain and Western blotting. The possibility that AR protein in spinal cord is expressed in tissue-specific form is proposed, being different from other androgen-dependent tissue. Northern blotting data showed that AR is expressed in not only rat spinal cord but also cerebrum and cerebellum, which are spared in SBMA. Then, specimens from 2 SBMA patients were examined and compared with those from normal controls (n = 4). AR was widely expressed in central nervous system. Anterior horn cells, which are severely affected in SBMA, were stained intensely. Even the remaining atrophic motor neurons in SBMA had AR. To our interest, the neurons of cranial nerves III, IV, VI, dentate nucleus, posterior horn and Onufrowicz nucleus etc., which are spared in SBMA, contained AR moderately. These data did not show any difference between SBMA and controls. Our immunohistochemical study showed that not only the neurons affected in SBMA but the unaffected in this disease process express AR. The question why motor neurons are selectively involved in SBMA if AR is present in almost neurons should further be clarified.
PMID: 8996845, UI: 97150086
J Mol Med 1996 Oct;74(10):555-562
Institute of Medical Genetics, A. Gemelli School of Medicine, Catholic University, Rome, Italy.
Spinal muscular atrophies (SMA) are a group of motor neuron diseases characterized by degeneration of anterior horn cells of the spinal cord and by muscular atrophy. Childhood-onset SMA is one of the most frequent autosomal recessive diseases and a leading cause of infant mortality. The underlying biochemical defect of SMA is unknown. Recently two genes have been isolated from the critical region at 5q13, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitor protein (NAIP) gene. Both genes are frequently deleted in SMA patients. NAIP is deleted in at least 45% of severely affected patients but less frequently in the milder forms. Homozygous deletions of exon 7 of SMN are found in approximately 95% of patients independently of clinical severity. A few point mutations and microdeletions in SMN have also been reported. This high frequency of deletions makes SMN analysis an important molecular diagnostic tool for childhood-onset SMA and greatly facilitates prenatal diagnosis. SMN analysis has also proven useful for the diagnosis of adult-onset SMA and variant forms. Although questions such as phenotype-genotype correlation must still be solved, the isolation of SMN and adjacent genes constitutes an important step towards the understanding of the molecular basis of the disease.
PMID: 8912176, UI: 97068988
J Neurol Sci 1996 Oct;142(1-2):12-16
First Department of Internal Medicine, Osaka Medical College, Japan.
Polyglutamine tracts encoded by trinucleotide CAG repeats have been found in some transcription factors. Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). To study the role of AR as a transcription factor in SBMA, we constructed AR genes encoding expanded polyglutamine tracts (repeat numbers = 52, 92, 132, and 212), and analyzed AR-induced transcriptional activation in NG108-15 cells. We found that AR-induced transcriptional activation gradually decreased with increasing glutamine repeat numbers, and polyglutamine expansion caused a specific reduction in transcription activity in motor neurons. However, the degree of reduction was slight in comparison with the normal AR gene and that of SBMA. Thus, subtle disorders of transcriptional control may occur in SBMA.
PMID: 8902713, UI: 97058393
Hum Mol Genet 1996 Sep;5(9):1253-1257
Department of Neurology, Nagoya University School of Medicine, Japan.
We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.
PMID: 8872464, UI: 97026285
Brain 1996 Aug;119( Pt 4):1099-1105
Prince of Wales Medical Research Institute, Randwick, Sydney, Australia.
Following conduction of an action potential there is a stereotyped sequence of changes in excitability as axons are initially refractory, then superexcitable and finally subexcitable. These activity-dependent oscillations in excitability subside over 100 ms and together constitute the recovery cycle. The present study was undertaken first to document the recovery cycle of sensory and motor axons of different threshold and, secondly, to compare the changes in sensory axons with those in motor axons. A computerized threshold-tracking system was used to measure recovery cycles in six healthy subjects; stimuli were applied to the median nerve at the wrist. Changes in the threshold required to produce an antidromic compound sensory action potential (CSAP) and an orthodromic compound muscle action potential (CMAP) of fixed amplitude (30%, 50% and 70% of maximal) were recorded following a single supramaximal conditioning stimulus. Normalized recovery cycles were identical for axons of different threshold, whether sensory or motor, and were reproducible on repeat testing. However, there were significant differences between the changes in sensory and motor axons, with greater supernormality and greater late subnormality in motor axons. The greater changes in motor axons could not be explained by differences in the strength-duration properties of sensory and motor axons. There are biophysical differences in the properties of sensory and motor axons and these differences may underlie the differential susceptibility of sensory and motor axons in peripheral nerve disorders.
PMID: 8813274, UI: 96408229
Rinsho Shinkeigaku 1996 Jul;36(7):892-894
[Article in Japanese]
Department of Neurology, School of Medicine, Nagoya University.
A 43-year-old man suffered from weakness of the upper limbs and easy fatigability. Low frequency (3 Hz) repetitive nerve stimulation (RNS) showed a marked waning with a maximum decrement of 20% of M wave amplitude. This remarkable waning was partially reduced by an administration of 60 mg bromopyridostigmine. High frequency RNS (30 Hz), however, did not induced waxing. Tensilon test and anti-AchR antibody were negative. The CAG repeat in androgen receptor gene was abnormally expanded ((CAG)n = 47), which confirmed a diagnosis of X-linked bulbar and spinal muscular atrophy. (BSMA). In some ALS patients, impaired neuromuscular transmission has been reported. The impaired neuromuscular transmission in ALS occurs in cases with rapidly progressive muscle wasting, suggesting that this abnormality is related to rapidly degenerating motor nerve endings. However, impaired neuromuscular transmission as seen in this patient has not been well documented in BSMA.
PMID: 8952360, UI: 97110166
Am J Med Genet 1996 May 3;63(1):218-222
Department of Pediatrics, Medical University of Lubeck, Germany.
Androgen insensitivity syndromes (AIS) are due to end-organ resistance to androgenic steroids in males leading to defective virilization of the external genitalia. The phenotype encompasses a wide array of genital ambiguity and may range from completely female to undervirilized but unequivocally male with infertility. This disorder is caused by mutations of the androgen receptor and is an X-linked recessive trait. We have studied 47 patients with AIS and have characterized the underlying molecular abnormality in the androgen receptor gene. Twenty patients had complete AIS and twenty-seven had partial AIS. Of the latter, 11 were of predominantly female phenotypic appearance and gender was assigned accordingly, while 16 were raised as males. Within the group of complete AIS, two patients had gross deletions within the gene, one had a small deletion, and one had an insertion. In the other patients with complete AIS, as well as all individuals with partial AIS, single nucleotide substitutions within the coding region were detected, each leading to an amino acid alteration. Seven codons were involved in more than one mutation in different cases. In addition, in one patient with spinal and bulbar muscular atrophy, an elongation of a glutamine-repeat was characterized. We conclude that mutations in the androgen receptor gene may be present throughout the whole coding region. However, our study provides evidence that several mutational hot spots exist.
PMID: 8723113, UI: 96298278
J Neurol 1996 May;243(5):388-392
Department of Neurological and Visual Sciences, Policlinico Borgo Roma, Verona, Italy.
Electrophysiological findings were studied in a family with spino-bulbar muscular atrophy (SBMA): the subjects were three male patients aged 58, 38 and 34 years and two female carriers aged 63 and 28 years. Diagnosis was proven at the molecular genetic level. Electromyography in the males showed spontaneous activity and neurogenic reorganization of the motor unit; motor nerve conduction was normal. Sensory action potentials were variably reduced in amplitude, but some were completely normal. Somatosensory evoked potentials, from both the upper and lower limbs, were invariably abnormal because involvement of the central pathways was observed. These findings are in agreement with histological investigations documenting lesions in the posterior columns. Brain-stem acoustic evoked potentials showed an increase in wave I latency. The electrophysiological data provide further evidence of the extent of sensory damage either in the central or the peripheral nervous system in SBMA patients, who otherwise have a constant clinical presentation of progressive motor neuron disease.
PMID: 8741078, UI: 96301843
Steroids 1996 Apr;61(4):172-175
Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.
Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46, XY individuals. The complete form of androgen insensitivity syndrome is characterized by 46, XY karyotype, external female phenotype, intra-abdominal testes, absence of uterus and ovaries, blindly ending vagina, and gynecomastia. There is also a group of disorders of androgen action that result from partial impairment of androgen receptor function. Clinical indications can be abnormal sexual development of individuals with a predominant male phenotype with severe hypospadias and micropenis or of individuals with a predominantly female phenotype with cliteromegaly, ambiguous genitalia, and gynecomastia. Complete or gross deletions of the androgen receptor gene have not been frequently found in persons with the complete androgen insensitivity syndrome, whereas point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain have been reported in both partial and complete forms of androgen insensitivity, with a relatively high number of mutations in two clusters in exons 5 and 7. The number of mutations in exon 1 is extremely low, and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain. The X-linked condition of spinal and bulbar muscle atrophy (Kennedy's disease) is characterized by a progressive motor neuron degeneration associated with signs of androgen insensitivity and infertility. The molecular cause of spinal and bulbar muscle atrophy is an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
PMID: 8732995, UI: 96311251
Mayo Clin Proc 1996 Apr;71(4):397-398
Division of Laboratory Genetics, Mayo Clinic Rochester, MN 55905 USA.
A novel type of genetic alteration, trinucleotide repeat amplification, is responsible for spinal and bulbar muscular atrophy.
PMID: 8637265, UI: 96197235
Front Biosci 1996 Mar 1;1:D59-D71
The Institute on Aging and the Department of Human Oncology, University of Wisconsin, Madison, WI 53706, USA
[Record supplied by publisher]
Androgens mediate a number of diverse responses through the androgen receptor, a 110 kD ligand-activated nuclear receptor. Androgen receptor expression, which is found in a variety of tissues, changes throughout development, aging, and malignant transformation. The androgen receptor can be activated by two ligands, testosterone and dihydrotestosterone, which bind to the androgen receptor with different affinities. This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands. The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element. The ability to confer androgen specific actions by the androgen response element may depend on other cell-specific transcription factors and cis-acting DNA elements in close proximity to it. Testosterone and dihydrotestosterone appear to act upon an identical nuclear receptor. However, in certain instances, they mediate different physiologic responses. For example, dihydrotestosterone, but not testosterone, is capable of mediating full sexual development of the male external genitalia. In some cases, the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location. For example, in male pattern baldness, activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal-epithelial actions, whereas other hair follicles continue to proliferate. In other cases, altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation.
PMID: 9159212
Mol Cell Endocrinol 1996 Mar 25;117(2):149-156
Department of Urology, University of Innsbruck, Austria.
Expansion of CAG trinucleotide repeats in androgen receptor gene is present in patients with a rare X-linked inherited form of motor neuron disorder termed Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). This is a late onset progressive disease often associated with mild signs of androgen insensitivity. Defects in androgen receptor (AR) action have been linked to the expansion of the CAG trinucleotide repeats and postulated to be the cause of the disease. We have identified a trinucleotide repeat of 45 in the N-terminus of the AR in two brothers with SBMA and several members in their family (range in the general population is 11-35). Treatment of the patients with androgens failed to improve their clinical symptoms and provided no hint of an anomalous function of the AR. Consistently, functional analysis of the mutant receptor showed hormone binding, transactivation and transrepression potentials identical to that of the wild-type receptor. These results together argue against SBMA being a loss of function mutation of the AR.
PMID: 8737374, UI: 96300438
Prenat Diagn 1996 Mar;16(3):262-265
Department of Neurology, University of Athens, Eginition Hospital, Greece.
X-linked spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disorder which is caused by an expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene. Two cases of prenatal testing for the disease in a Greek family are reported. An affected male died in his late 50s of this disorder and his 30-year-old daughter (an obligate carrier) asked for prenatal testing for SBMA. DNA analysis revealed that she indeed carried an expanded allele of 40 repeats, as well as a normal size allele of 24 repeats. Prenatal diagnosis of SBMA was performed when, on two successive pregnancies, two male fetuses with the expanded (CAG)n allele were found.
PMID: 8710782, UI: 96290125
J Neurol Sci 1996 Feb;135(2):140-148
Neurological Department, Santa Maria Nuova Hospital, Reggio Emilia, Italy.
We report the clinical, neurophysiological, neuropsychological, neuropathological and molecular findings in a large family with X-linked bulbar and spinal muscular atrophy (X-BSMA). Molecular study, performed in 28 family members, showed an increase in the number of CAG repeats in 6 affected males (including 2 presymptomatic patients), and in 10 females, of whom 5 were obligate carriers. All symptomatic patients showed, besides the typical manifestation of X-BSMA, neurophysiological signs of sensory nerve involvement, and abnormal findings in neuropsychological tests. Sural nerve biopsy, performed in two patients, was consistent with axonal atrophy and slow-rate degeneration, with secondary demyelination. Neurophysiological alterations were also present in 6 out of 8 carriers, consisting of neurogenic EMG changes in 3 cases and abnormal sensory action potentials (SAP) and reduced conduction velocity of the sural nerve in 3 cases. Abnormalities of at last two neuropsychological tests were found in 6 out of 8 carriers. Alterations of the sensory nerves in X-BSMA patients have been previously reported in some cases; however, we demonstrate for the first time sensory nerve involvement also in carriers. Evidence of central nervous system involvement, with neuropsychological impairment in all symptomatic patients and in some carriers, is another feature of this family, not previously reported in X-BSMA. In spite of the variable phenotypic features, the number of CAG repeats ranged from 40 to 44 in the affected patients, indicating that phenotypic expression was not related to the size of the mutation, but was probably age-related.
PMID: 8867070, UI: 97020710
J Neurol Sci 1996 Feb;135(2):149-157
Centre for Hormone Research, Royal Children's Hospital, Parkville, Victoria, Australia.
Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.
PMID: 8867071, UI: 97020711
Hum Mutat 1996;8(1):32-37
Institute of Medical Genetics, University of Zurich, Switzerland.
Expansion of trinucleotide repeats has now been associated with eight inherited diseases: X-linked spinal and bulbar muscular atrophy, two fragile X syndromes, myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral pallidoluysian atrophy and Machado-Joseph disease. It has been shown that these expanded DNA repeats are unstable in number when transmitted from parents to offspring ("meiotic instability"), while somatic variation in repeat number has also been found in the fragile X syndrome and myotonic dystrophy. Moderate meiotic instability has been demonstrated in X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). In order to determine if the expanded CAG repeat in SBMA also shows somatic instability, we compared different tissues from two patients with SBMA. We then examined the in vitro stability of the CAG repeat expansion by analyzing fibroblast cell cultures. Length comparison of expanded CAG repeats from all these materials clearly demonstrates that the CAG trinucleotide repeat in SBMA does not exhibit somatic variation.
PMID: 8807333, UI: 96400957
Am J Hum Genet 1995 Dec;57(6):1503-1505
Publication Types:
PMID: 8533782, UI: 96065041
Ugeskr Laeger 1995 Nov 13;157(46):6440-6441
[Article in Danish]
Department of Internal Medicine, Armed Forces Hospitals Southern Region, Khamis Mushayt, Kingdom of Saudi Arabia.
A case of X-linked recessive bulbospinal neuronopathy is reported. Neurophysiological findings were consistent with chronic partial denervation (motor axonopathy) and large fibre sensory axonopathy. DNA analysis showed an abnormal increased size of tandem CAG repeats.
PMID: 7483104, UI: 96079745
Trends Neurosci 1995 Oct;18(10):459-461
University of Pennsylvania School of Medicine, Dept of Neurology, Philadelphia 19104, USA.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the androgen-receptor gene. The length of this repeat varies as it is passed down through SBMA families, and correlates inversely with the age of onset of the disease. The motor-neuron degeneration that occurs in this disease is probably caused by a toxic gain of function in the androgen-receptor protein. Subsequent to the identification of the mutation in SBMA, other inherited neurodegenerative diseases have been found to be caused by the expansion of CAG repeats in the coding regions of other genes. Because these diseases probably share a common pathogenesis, investigation of SBMA might help to determine a general mechanism of neuronal degeneration.
PMID: 8545913, UI: 96104231
Ital J Neurol Sci 1995 Oct;16(7):467-471
Divisione di Neurologia, Istituto Nazionale Neurologico C. Besta, IRCCS, Milano.
Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is a rare X-linked motoneuron disorder with variable signs of androgen insensitivity. It is associated with the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. We here report our clinical and molecular findings in two Italian families with Kennedy's disease. The increased size of the CAG repeat was demonstrated in four affected males and seven carrier females.
PMID: 8749704, UI: 96307515
Lancet 1995 Oct 28;346(8983):1162
Comment on: Lancet 1995 Sep 16;346(8977):741-2
PMID: 7475624, UI: 96036447
Arq Neuropsiquiatr 1995 Sep;53(3-A):471-474
[Article in Portugese]
Departamento de Clinica Medica, Hospital de Clinicas, Universidade Federal do Parana (UFPr), Curitiba.
We report two cases of Kennedy's disease (muscle weakness, amyotrophy, intentional tremor, endocrine abnormalities, and denervation signs at electromyography). This entity must be differentiated from other motor neuron disorders by the genetic pattern (X-liked recessive), gynecomastia, testicular atrophy, oligospermia and good prognosis. A discussion about the clinical pattern and evolution is made.
PMID: 8540824, UI: 96085601
J Androl 1995 Jul;16(4):299-303
Department of Population Dynamics, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
The clinical and pathophysiologic features of AIS provide a human model for understanding the role of androgen and its receptor in the induction and maintenance of male sex differentiation and function. Upon inspection, one is immediately impressed by the diverse nature of the mutations involved in the spectrum of AIS and the heterogeneous distribution of these mutations throughout the coding region of the AR gene. Because of the large number and diverse array of these naturally occurring mutations and their associated clinical phenotypes, there is great potential for understanding the structure-function relationships of AR from the in vitro expression of the mutant receptors in various cell lines. Future studies will be directed toward understanding the coordinate functional domains of AR, AR binding to specific androgen response elements, AR dimerization, AR phosphorylation, and AR interaction with accessory proteins that direct cell- and temporal-specific regulation of gene transactivation.
PMID: 8537246, UI: 96048272
J Steroid Biochem Mol Biol 1995 Jun;53(1-6):443-448
Department of Endocrinology, Erasmus University, Rotterdam, The Netherlands.
Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
PMID: 7626493, UI: 95352489
Arch Phys Med Rehabil 1995 May;76(5 Spec No):S3-S9
Thomas Jefferson University, Philadelphia, PA 19107, USA.
This article of the Self-Directed Physiatric Education Program to assist practitioners and trainees in physical medicine and rehabilitation identifies the anatomy and physiology of nerve, neuromuscular junction, and muscle as they relate to rehabilitation of diseases affecting these structures. Structural relationships of the spinal roots, peripheral nerves, motor units, and muscle fibers are outlined, with structural, functional, and electrodiagnostic correlations. Features of nerve and muscle biochemistry and physiology are reviewed as they relate to common neurological diseases, age, and sex. The spontaneous potentials, motor unit activities, and nerve conduction abnormalities found in diseases of nerve and muscle also are described.
Published erratum appears in Arch Phys Med Rehabil 1995 Jul;76(7):704
PMID: 7741627, UI: 95260210
J Neurol Sci 1995 May;129 Suppl:56-57
Department of Neurology, Graduate School of Neurosciences Amsterdam, Netherlands.
Kennedy disease is caused by an enlarged trinucleotide repeat sequence within the androgen receptor gene. We report here seven male patients with a benign motor neuron syndrome highly analogous to Kennedy disease but with a normal trinucleotide repeat.
PMID: 7595622, UI: 96059146
J Neurol Neurosurg Psychiatry 1995 May;58(5):625-628
Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Australia.
Four patients are described who developed sensorimotor neuropathy while being treated with simvastatin and had complete or partial resolution of clinical abnormalities after withdrawal of treatment. In one case onset was within days of commencing treatment, but in two cases symptoms did not develop for two years. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Clinical evidence of proximal and distal weakness and muscle fasciculations and persistent abnormalities of sensory conduction after recovery suggest the possibility of toxic damage to anterior horn cells and dorsal root ganglia. Thirty eight other cases with symptoms suggestive of peripheral neuropathy have been reported to the Australian Adverse Drug Reactions Advisory Committee, 22 of whom recovered after cessation of treatment; in five cases there was recurrence after re-exposure to the drug. Simvastatin should be considered among the causes of peripheral neuropathy, and the drug should be withdrawn if patients receiving it develop muscle weakness or sensory disturbances.
PMID: 7745415, UI: 95264144
Neurology 1995 Apr;45(4):699-704
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Distal spinal muscular atrophy is a rare lower motor neuron disorder that may be difficult to distinguish clinically from type II Charcot-Marie-Tooth disease. We report on clinical and pathologic findings in 13 members of a four-generation extended family with autosomal dominant distal spinal muscular atrophy. The patients developed a slowly progressive lower motor neuron disorder involving mainly the distal lower extremities; onset was from the second to fourth decades. Electromyography and muscle biopsy findings were indicative of motor denervation. Combined silver/cholinesterase/immunocytochemical staining of intramuscular nerve revealed abundant collateral axonal branching in mild disease but marked loss of terminal motor endplate innervation in the more severe state, suggesting decreased growth of motor axon collaterals with disease progression. Multipoint DNA linkage analysis showed that this family's disorder is not linked to the chromosome 5q11.2-13.3 spinal muscular atrophy locus.
Grant support:
PMID: 7723957, UI: 95240852
J Clin Endocrinol Metab 1995 Feb;80(2):508-516
Center for Hormone Research, Royal Children's Hospital, Victoria, Australia.
We have investigated androgen-binding properties of the androgen receptor (AR) in cultured suprapubic skin fibroblasts from six subjects with Kennedy's disease (X-linked spinal and bulbar muscular atrophy). Binding of the synthetic androgen methyltrienolone (R1881) was measured in a monolayer assay, and Scatchard analysis was performed to determine the total number of binding sites and the apparent binding affinity (Kd) of the AR for androgen. Five of the six subjects investigated had an abnormal apparent binding affinity, with Kd values ranging from 0.34-11.7 nmol/L, more than 2 SD from the mean of the normal range (0.19 +/- 0.06 nmol/L). In this group of six patients, there was a significant correlation between the AR Kd and the severity of testicular atrophy and gynecomastia. The number of CAG repeats in the expanded region of exon A of the AR gene was determined in all subjects from whom suprapubic skin fibroblasts were cultured and an additional 12 subjects with Kennedy's disease. In the total group of 18 subjects investigated, there was a trend for an increasing number of CAG repeats associated with decreasing age at onset of different symptoms; however, this correlation was not statistically significant. Thus, we report for the first time a quantitative abnormality of the AR apparent binding affinity in subjects with Kennedy's disease, which appears to be related to the severity of the symptoms of androgen insensitivity.
PMID: 7852512, UI: 95155533
Hum Mol Genet 1995 Feb;4(2):303-305
Molecular Biology Program, USC, Los Angeles 90089-1340, USA.
Using a modified sperm typing protocol, the mutation frequency of the CAG repeat region at the androgen receptor locus has been measured using a rare semen sample from an individual with spinal and bulbar muscular atrophy (SBMA). Among 258 X chromosome-containing sperm, 19% had a repeat number equal to the donor's somatic DNA (47 repeats), 66% were expansions and 15% were contractions. The average expansion was 2.7 repeats. More than half of the expansions involved one or two repeats; the largest was 11 repeats. 68% of the contractions were also one or two repeats but six (16%) were very large (12-25 repeats). One contraction generated an allele in an intermediate size range (33-39 repeats). Such alleles have not been observed among more than 900 normal and SBMA X-chromosomes that have been examined. Comparison of the SBMA sperm typing results with mutation frequency data on normal alleles supports the hypothesis that trinucleotide repeat expansions may have a different molecular origin than contractions.
Grant support:
PMID: 7757084, UI: 95276747
Am J Med Genet 1995 Jan 2;55(1):105-111
Istituto di Tecnologie Biomediche Avanzate CNR, Milano, Italy.
An increase in the number of (CAG)n repeats in the first coding exon of the androgen receptor (AR) gene has been strongly associated with Kennedy disease (KD) (spinal and bulbar muscular atrophy). This is an X-linked hereditary disorder characterized by motoneuron degeneration occurring in adults together with gynecomastia and hyperestrogenemia. We have performed AR gene molecular analysis in several members of a large family with KD as well as in 25 sporadic patients suffering from heterogeneous motoneuron disease (MND). An increase in the length of the (CAG)n repeats was detected, as expected, in all the affected males and in obligatory carrier females, some of which had minor signs of lower motoneuron involvement. There was only one possible exception, one young male with initial signs of the disease, who had an apparent normal length allele. An increased pathological allele was also found in 3 patients with MND. This indicates that the analysis of (CAG)n repeats of the AR gene plays a role in the differential diagnosis of this heterogeneous group of neurological diseases.
PMID: 7702080, UI: 95216643
Crit Rev Eukaryot Gene Expr 1995;5(2):97-125
Department of Human Oncology, University of Wisconsin, Madison 53792, USA.
The action of androgens in regulating development and growth is mediated by androgen receptor (AR). AR is a member of the steroid hormone receptor superfamily, a class of receptors that function through their ability to regulate the transcription of specific genes. The AR is located in various target tissues, with its levels and activity altered with the onset of various cellular events (e.g., sexual development, malignant transformation). The modulation of AR levels occurs through a number of mechanisms, including transcription, and is regulated by various factors (e.g., androgens). The ability of AR to modulate gene transcription is through its interaction with specific DNA sequences located near or within the target gene promoter. The importance of the AR in reproductive physiology has been emphasized by the finding of AR mutations, leading to a variety of disorders, including testicular feminization syndrome. In this article, we review the structure and function of AR and the role AR plays in the function of the mammalian system.
Grant support:
PMID: 8845584, UI: 96114474
Rev Neurol (Paris) 1994 Dec;150(12):854-857
[Article in French]
Clinique Neurologique, C.H.R.U. de Nantes.
Four men and one woman of the same family with Kennedy-type-bulbo-spinal amyotrophy have been followed up for 7 to 20 years. The genetic marker: insertion of repeated sequences of trinucleotide Cytosine-Adenine-Guanine described by Fischbeck and La Spada in Nature (1991), in the coding region of the androgen receptor gene, on the long arm of X chromosome, has been demonstrated here by DNA extraction and PCR amplification.
PMID: 7676123, UI: 95406558
J Pediatr Endocrinol 1994 Oct;7(4):275-282
Department of Endocrinology & Reproduction, Erasmus University Rotterdam, The Netherlands.
Over the past three decades, a great deal of evidence has accumulated in favor of the hypothesis that steroid hormones act via regulation of gene expression. The action is mediated by specific nuclear receptor proteins, which belong to a superfamily of ligand-modulated transcription factors that regulate homeostasis, reproduction, development and differentiation. This family includes receptors for steroid hormones, thyroid hormones, hormonal forms of vitamin A and D, peroxisomal activators, and ecdysone. Molecular cloning and structure/function analyses have revealed that all members of the steroid/thyroid hormone/retinoic acid receptor family have a similar functional domain structure: a variable N-terminal region, which is involved in modulation of gene expression; a short well-conserved DNA-binding domain, which is crucial for recognition of specific DNA sequences and for receptor dimerization; and a partially conserved C-terminal ligand-binding domain, which is important for hormone binding and also for receptor dimerization and transactivation. In contrast to other members of the receptor superfamily steroid hormone receptors form transient complexes with several heat shock proteins. This interaction promotes proper folding and stability of the receptor molecule. Hormone binding induces a conformational change in the receptor molecule and simultaneously a dissociation of all heat shock proteins, which results in DNA-binding of the hormone-receptor complex.
PMID: 7735364, UI: 95253284
Muscle Nerve 1994 Sep;17(9):1010-1020
Department of Neurology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Neuropathy was classified physiologically and histologically as normal, axonal, demyelinative, or indeterminate using specific motor nerve conduction (NC) and sural sensory nerve biopsy (NB) criteria. Physiological and histological diagnoses were concordant in 63%, and minimally discordant in 14% of patients. The most important discordant patients were 6 with demyelinative neuropathy, 4 by NC, of which 2 were pure motor syndromes, and 2 by NB, both predominantly sensory syndromes. In the 55 patients with predominant axonal degeneration on biopsy, the extent of NC slowing was determined. As compound motor and sensory nerve action potential (CMAP and SNAP) amplitude declined, distal motor latency increased, whereas motor and sensory conduction velocity (CV) did not. Minimum F response latency increased as motor CV decreased, more in lower than upper extremity nerves. We conclude that: (1) except for sensory neuropathy, routine motor NC studies generally suffice in identifying demyelinative neuropathy; (2) NC slowing in axonal neuropathy is usually slight but may result in significantly prolonged distal motor latencies when CMAP amplitude is very low, and prolonged F wave latency when motor CV is slightly low; and (3) The physiologic criteria employed in this study rarely misclassifies neuropathy as demyelinative in patients with predominant axon loss on biopsy.
Comments:
PMID: 8065388, UI: 94344170
Nucleic Acids Res 1994 Aug 11;22(15):3181-3186
Department of Biochemistry, University of Arizona, Tucson 85724.
Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.
PMID: 8065934, UI: 94344784
Baillieres Clin Neurol 1994 Aug;3(2):431-445
Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
The spinal muscular atrophies (SMAs) are defined as a group of inherited disorders sharing the common pathological feature of degeneration of the anterior horn cells of the spinal cord and, in some cases, additionally of the bulbar motor nuclei. They are classified according to clinical features, including severity and distribution of muscle weakness and on their modes of inheritance. The SMAs are not uncommon: SMA type I (severe, acute infantile SMA) alone has a gene frequency in the UK estimated at 0.006. Together they represent a significant source of morbidity and mortality. Over the past 3 years, two major advances have been made towards understanding the molecular basis of these clinically heterogeneous disorders. First, in 1990, it was reported that all three forms of childhood-onset proximal SMA were linked to probes mapping to the proximal long arm of chromosome 5. Significant progress has been made towards isolating the gene or genes responsible, and a protocol for prenatal disease prediction in families with a previously severely affected child has been established. Second, in 1991, the molecular defect in adult-onset X-linked spinal and bulbar muscular atrophy was defined as an expansion of a (CAG)n trinucleotide repeat which encodes a string of glutamine residues in the first exon of the androgen receptor. Little progress has been made in elucidating the molecular pathology of the other SMAs. None of them has been linked to chromosome 5q markers, or indeed to markers elsewhere; the conditions are rare and pedigrees generally small. When the gene (or genes) on proximal 5q underlying SMA types I, II and III is cloned, mutations in this can then be sought in the other SMAs. The product of the chromosome 5q gene presumably plays a crucial role in maintaining the integrity of motor neurones, so determination of its structure and function may well have consequences far beyond those pertaining to the inherited SMAs. The identification of pathogenic mutations in the SOD-1 gene in familial amyotrophic lateral sclerosis is of great interest, although it is not clear that similar mechanisms contribute to the more common sporadic form of the disease.
PMID: 7952856, UI: 95040627
Muscle Nerve 1994 Apr;17(4):419-423
Department of Neurology, University of Michigan Medical Center, Ann Arbor 48109-0316.
A 43-year-old male was referred by a veterinarian who evaluated his dog for a seizure and suspected a toxic lead exposure for both. He refurbished houses, removing old paint, and complained of decreased cognition, fatigue, and muscle cramps. He had a depressed affect, postural tremor, right arm weakness with partial denervation on EMG, and borderline-low sensory nerve action potential (SNAP) amplitudes. A mild anemia and elevated serum and urine lead levels supported a diagnosis of lead neuropathy. Chelation therapy increased urine lead excretion without symptomatic improvement. His brother worked part-time with him and developed similar findings, but also had difficulty chewing, dysphagia, perioral twitching, gynecomastia, and multifocal denervation of extremity and facial muscles. His lead levels were not elevated, but an androgen receptor mutation identified on the X chromosome for both brothers confirmed the diagnosis of X-linked bulbospinomuscular atrophy (Kennedy's disease).
PMID: 8170488, UI: 94224252
Acta Neurol Scand 1994 Mar;89(3):214-219
Laboratory of Clinical Neurophysiology, Rigshospitalet (the National Hospital) Copenhagen, Denmark.
We examined 8 men with X-linked recessive bulbospinal neuronopathy. Quantitative electromyography showed large amplitude motor unit action potentials of prolonged duration and increased polyphasia. There was a pronounced loss of motor units in all but one muscle at maximal volition even in muscles with normal or only mildly decreased force. Denervation activity was present in 53% sampled limb muscles, and fasciculation was recorded in 33% of limb muscles. Nerve conduction studies showed small amplitude sensory action potentials in 6 out of 8 patients. The motor and sensory conduction velocity was normal or borderline slow. The electrophysiologic findings were consistent with chronic partial denervation (motor axonopathy) combined with large fibre sensory axonopathy.
PMID: 8030404, UI: 94303400
Muscle Nerve 1994 Feb;17(2):198-205
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-6965.
Diagnosis of multifocal motor neuropathy (MMN), a syndrome characterized by progressive asymmetric weakness with intact sensation, is important because the disorder often responds to treatment. Multifocal partial motor conduction block (PMCB) has been emphasized as a cardinal feature in the diagnosis of this syndrome, but detailed nerve conduction studies are not available. Nine patients, ages 28-58, had chronic, progressive, asymmetric, predominantly distal limb weakness for 5-18 years. Sensation was normal and reflexes were reduced asymmetrically. Although all 9 demonstrated PMCB localized to short nerve segments, additional features of multifocal motor demyelination were present, including temporal dispersion (5 patients), segmentally reduced motor nerve conduction velocity (7 patients), prolonged distal motor latency (4 patients), and prolonged F-wave latency (9 patients). The strength of all patients improved after treatment with human immune globulin. A reduction in the degree of PMCB or an increase in the distal motor amplitude or both accompanied the clinical improvement. These studies suggest that patients with MMN demonstrate widespread evidence of motor demyelination in addition to the well-described PMCB, and that reduction of PMCB accounts for the increase in strength following therapy.
PMID: 8114790, UI: 94158936
Hum Mol Genet 1994 Jan;3(1):73-78
Genome Analysis Laboratory, Imperial Cancer Research Fund, London, UK.
The recent observation that the mutation underlying a number of genetic diseases including fragile sites, FRAXA and FRAXE (associated with mental retardation), myotonic dystrophy, spinal and bulbar muscular atrophy (Kennedy's disease), Huntington's disease and spinocerebellar ataxia type 1 are caused by the expansion of a trinucleotide repeat sequence will lead to interest in the identification of such sequences in regions related to other diseases. We report here the identification of all ten classes of trinucleotide repeats within a 2 Mbp region of 4p16.3 containing the Huntington's disease (HD) gene. Fifty one triplet repeats were identified and localised on a high resolution restriction map of a cosmid contig covering this region. This included the triplet repeat (CAG)n, which has subsequently been shown to be expanded in Huntington's disease patients.
PMID: 8162055, UI: 94214480
Hum Mutat 1994;3(1):19-24
Institute of Genetics, University of Cologne, Germany.
The triplet repeat sequences (CGG)n, (GCT)n, and (CAG)n, which naturally occur in the human genome, can be autonomously expanded in human DNA by an as yet unknown mechanism. These in part excessive expansions have been causally related to human genetic diseases, the fragile X (Martin-Bell) syndrome, to myotonic dystrophy (Curschmann-Steinert), to spinal and bulbar muscular atrophy (Kennedy disease), and recently to Huntington disease. A GCC trinucleotide repeat was found to be expanded and methylated in the fragile site FRAXE on the human X chromosome. These findings were associated with mental retardation (Knight et al., 1993). In spinocerebellar ataxia type 1 (SCA1), a polymorphic CAG repeat was found to be unstable and expanded in individuals with that disease (Orr et al., 1993). We have demonstrated in in vitro experiments that the synthetic oligodeoxyribonucleotides (CGG)17, (CGG)12, (GCC)17, (CG)25, (CTG)17, or (CAG)17 plus (GTC)17, in the absence of added natural DNA, can be expanded with Taq polymerase in the polymerase chain reaction (PCR). Some expansion can already be detected after 4 PCR cycles. The E. coli Klenow DNA polymerase also functions in a similar amplification and expansion reaction performed at 37 degrees C without cycling. Other oligodeoxyribonucleotides, like, (CGG)7, (CGGT)13, or (TAA)17, are devoid of this property or have very low activity. The cytidine-methylated polymers (GCC)17 or (CG)25 yield expansion products of considerably reduced chain lengths. The expansion of the polymer (CGG)17 is affected by cytidine methylation to a lesser degree. A specific sequence and/or secondary structure and high CG content appear to be requirements for this expansion reaction by a possible slippage mechanism.
PMID: 8118462, UI: 94163184
FEBS Lett 1993 Nov 1;333(3):248-250
Institute for Genetics, University of Cologne, Germany.
The seemingly autonomous amplification of naturally occurring triplet repeat sequences in the human genome has been implicated in the causation of human genetic disease, such as the fragile X (Martin-Bell) syndrome, myotonic dystrophy (Curshmann-Steinert), spinal and bulbar muscular atrophy (Kennedy's disease) and Huntington's disease. The molecular mechanisms underlying these triplet amplifications are still unknown. We demonstrate here that a synthetic (CGG)17 oligodeoxyribonucleotide can be utilized as hybridization probe to visualize some of the triplet repeats in the human genome. This technique may help in studies aimed at the elucidation of the amplification mechanism.
PMID: 8224187, UI: 94039769
Neurology 1993 Nov;43(11):2424-2425
Comment on: Neurology 1993 Apr;43(4):791-4
PMID: 8232979, UI: 94050659
Nippon Rinsho 1993 Sep;51(9):2414-2419
[Article in Japanese]
Department of Neurology, Osaka University Medical School.
X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.
PMID: 8411722, UI: 94017259
No To Shinkei 1993 Jul;45(7):661-667
[Article in Japanese]
Department of Neurology, Chiba University, Japan.
The distributions of androgen receptor (AR) like protein were studied immunohistochemically in the central nervous system of rat and human medulla and spinal cord. Six male rats, weighing 160-180 g and medulla and spinal cord from three non-neurological human cases were used. The rats were perfused through the heart and fixed with 4% paraformaldehyde. Small blocks of the medulla and spinal cord from the human samples were also fixed with the same manner. Tissue sections of 20 microns were incubated with primary antibody (NH27; anti-human androgen receptor) and processed by the peroxidase-avidin-biotin complex methods. The specificity of this antibody was analyzed by Western blotting. A band of approximately 95 kDa which corresponds to AR and other several bands which may be degradating products were seen. Immunohistochemical examination of the rat brain and spinal cord revealed that positive neurons were localized in the amygdala, hypothalamus, motor nuclei of cranial nerves in brainstem, reticular formation of pons and medulla, Purkinje cells and anterior horn cells. The localizations of the immunoreactivity were chiefly in the cytoplasm as well as the processes. In the non-neurological human tissues, hypoglossal nucleus and anterior horn cells had positive immunoreactivity for AR like protein. They were localized in the cytoplasm and their processes. The abnormality of CAG repeat site of gene which code the androgen receptor has been recognized in X-linked spinal and bulbar muscular atrophy (Kennedy-Alter-Sung syndrome; KAS).
PMID: 8398387, UI: 94001108
Neurology 1993 Apr;43(4):791-794
Department of Neurology, Ohio State University, College of Medicine, Columbus 43210.
We confirmed a mutation of the androgen receptor gene as the cause for Kennedy's disease, also called "X-linked recessive spinal and bulbar muscular atrophy" or "bulbospinal neuronopathy." The mutation is characterized by an increased size of a polymorphic tandem CAG repeat within the first exon of the gene. The study population consisted of 17 patients from seven families (five distinct kinships and two isolated cases). Two patients were as yet asymptomatic and had normal examinations. Four carrier females showed the mutant as well as the normal allele; none showed clinical features of Kennedy's disease. There was no large expansion of the mutation observed in three generations of one family. Phenotypic expression between and within families was variable and not related to the size of the mutation. This contrasts with the gene mutations found in myotonic dystrophy and fragile X syndrome, where increased severity of disease correlates with the number of tandem triplet repeats. The findings reported here appear to explain the failure to find genetic anticipation in Kennedy's disease. The DNA test for Kennedy's disease can now be used for definitive diagnosis and carrier detection. In addition, mutation analysis allows early detection, which has implications for potential treatment.
Comments:
PMID: 8469342, UI: 93226119
Aust N Z J Med 1993 Apr;23(2):187-192
Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Vic., Australia.
Kennedy's disease (X-linked spinal and bulbar muscular atrophy) is an inherited form of motor neuron disease that may be diagnosed genetically using the polymerase chain reaction (PCR). This form of motor neuron disease principally affects the proximal limb girdle muscles as well as those involved with deglutition and phonation. Onset is usually late, in the fourth to fifth decades of life, and progression is slow. Moderate gynaecomastia and testicular atrophy are usually present, suggesting a defect in androgen receptor function. Being inherited in an X-linked recessive manner, only males are affected, with females as the unaffected carriers. The genetic abnormality that causes Kennedy's disease is an enlargement of the androgen receptor (AR) gene, which is located on the proximal long arm of the X chromosome. In patients with this disease, a region in the gene containing repeated CAG triplet nucleotides is approximately twice the size of that found in normal people. Using PCR to amplify this region of the AR gene, this study confirms this genetic mutation in 12 males from eight different families. All these families live on the east coast of Australia. This mutation was not found in five patients with other forms of motor neuron disease. Twelve heterozygote females, the daughters of affected males and carrier females, have also been identified. In addition, there are 14 asymptomatic and as yet untested sons of carriers, ranging in age from less than one year to over 40 years of age. Each has a 50% chance of inheriting the abnormal gene from his mother and thus developing Kennedy's disease.
PMID: 8517843, UI: 93298112
J Pediatr 1993 Feb;122(2):169-185
Greenwood Genetic Center, South Carolina 29646.
The fragile X syndrome is recognized as the most common heritable condition resulting in mental retardation. The disabilities are substantial, and therefore early detection is mandatory to assist with reproductive counseling of families in which the fragile X syndrome has occurred. Highly accurate, direct DNA diagnostic testing can now be performed to diagnose the fragile X syndrome without the involvement of individual family members, as was the situation with the use of DNA linkage analysis. Such testing is rapidly becoming a standard diagnostic tool for screening of individuals with suspected fragile X syndrome, of potential unaffected carriers, and of patients with undefined mental retardation. Fragile X testing should be considered for all children with developmental delay of unknown cause. Autistic children will occasionally be found to have mutations in FMR-1. Detection of affected individuals will allow early intervention for these individuals and will assist families with their reproductive decisions (including prevention) in subsequent offspring. An understanding of the molecular genetics of fragile X syndrome has resulted in the resolution of the Sherman paradox and is the first molecular characterization of a chromosomal fragile site, a finding that almost certainly will be important in understanding the cause of chromosomal rearrangements involving fragile sites. In addition, molecular details of the fragile X mutations have yielded insight into "heritable unstable elements," of which the fragile X chromosome is one of the first characterized examples. Thus a similar molecular mechanism involving a trinucleotide repeat may explain the genetics of myotonic dystrophy and spinal-bulbar muscular atrophy (Kennedy disease); it seems reasonable to assume that other genetic diseases also may result from disruption of genes by inherited unstable elements.
PMID: 8429429, UI: 93155824
Acta Neurol Scand 1993 Jan;87(1):56-61
Department of Neurology, Medical School Hospital, Aegean University, Bornova, Izmir, Turkey.
Two cases of X-linked bulbo-spinal muscular atrophy and one sporadic case with the same clinical features are presented. All three cases were extensively studied by electrophysiological methods. One of the patients showed some transient weakness, which was partly improved by pyridostigmin. In this patient the Decrement test and jitter revealed a mild degree of motor-end plate dysfunction. Clinical and electrophysiological findings obtained from all three patients suggest that in Kennedy syndrome cell bodies of group IA muscle afferents are also affected selectively, with other peripheral afferents.
PMID: 8424313, UI: 93142513
Clin Exp Neurol 1993;30:61-65
Department of Neurology, Alfred Hospital, Melbourne.
Kennedy's disease is a form of progressive spinal and bulbar muscular atrophy of adult onset. This paper describes a case of Kennedy's disease and discusses the laboratory diagnosis and the underlying genetic mechanism. Three other neurological diseases, Huntington's disease, myotonic dystrophy and fragile X syndrome, which have similar genetic defects, are also discussed.
PMID: 7712629, UI: 95228213
Zh Nevropatol Psikhiatr Im S S Korsakova 1993;93(2):84-86
[Article in Russian]
The authors describe 4 cases of Kennedy's medullo-spinal amyotrophy (BSA) which is a genetically determined disease with mutant gene inheritance by the recessive type with X chromosome cohesion. The disease largely shows up by the impairment of the nervous system in the form of BSA. However, the clinical picture is also marked by the derangement of the mesenchymal (Dupuytren's contracture) and endocrine systems (gynecomastia).
PMID: 8048316, UI: 94324251
Neurology 1992 Dec;42(12):2300-2302
Department of Neurology, Nishi-Ojiya Byoin National Sanatorium, Niigata, Japan.
X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by androgen receptor gene mutations with an increased number of tandem CAG repeats in exon 1. We investigated the increased number of CAG repeats in androgen receptor genes of 19 SBMA patients and found that this correlated strongly with the age at onset of muscle weakness. Thus, SBMA is the first genetic disease in which a strong correlation between the degree of genetic abnormality (number of CAG tandem repeats) and clinical phenotypic expression is demonstrable. The results further indicate that androgen gene mutation is directly involved in the degeneration of motor neurons.
PMID: 1461383, UI: 93096171
J Neurol Sci 1992 Oct;112(1-2):133-138
Department of Human Genetics, University of Manitoba, Winnipeg, Canada.
Herein we describe a family with X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), an adult onset neuromuscular disease characterized by slow progression, predominant proximal and bulbar muscle weakness. One frequent association is the appearance of gynecomastia. This disorder was previously shown to be linked to the locus DXYS1 on the proximal long arm of the X chromosome. Recently, a report implicated a mutation at the N-terminus of the androgen receptor gene involving amplification of CAG repeats as the cause of X-linked SBMA. We studied this region of the androgen receptor in a kindred clinically suspected but not confirmed of having X-linked SBMA by the polymerase chain reaction (PCR) followed by Southern analysis and DNA sequencing. The mutated allele was found to have an increased number of 51 CAG repeats confirming the clinical diagnosis of SBMA. Normal individuals revealed 23 repeat numbers within the normal range, while another unrelated X-linked SBMA patient had an enlarged CAG repeat region. The carrier or disease status could be established or confirmed in 12 individuals of this family on the basis of detecting normal and disease alleles reflected by the number of CAG repeats.
PMID: 1469423, UI: 93107986
Hum Mol Genet 1992 Jul;1(4):255-258
Laboratoire de Genetique Moleculaire des Eucaryotes du CNRS, Strasbourg, France.
Increased length of a protein-coding CAG repeat within the androgen receptor gene appears to be the only type of mutation responsible for spino-bulbal muscular atrophy (SBMA or Kennedy disease). We have analysed a large 4-generation SBMA family and found that the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. Our results suggest also limited somatic instability of the abnormal allele, with observable variation of up to 2-3 repeats. This indicates that the behavior of the CAG repeat is similar to that observed for small premutations in the fragile X syndrome, or small abnormal alleles in myotonic dystrophy, two diseases which are caused by expansion of an unstable trinucleotide repeat.
PMID: 1303195, UI: 93265034
J Med Assoc Thai 1992 Jun;75(6):369-373
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
The first case of X-linked recessive bulbospinal neuronopathy in a Thai family is described. Clinical features of this entity were discussed. Although two members of this family had classical features of X-linked recessive bulbospinal neuronopathy, there were some differences in distribution of weakness among the affected members. This variation among the members of the affected family was firstly described. The clinical features of this disease especially the associated gynecomastia and essential tremors are distinctive and it is possible to diagnose it even in a sporadic case. Although, the prominent feature of the disease is atrophy and fasciculation of muscles, this entity is not a pure anterior horn cell disorder and should be better classified as a multisystem disorder due to multiple organ involvement.
PMID: 1487685, UI: 93139688
Biochem Biophys Res Commun 1992 Jan 31;182(2):507-513
Department of Medicine III, Osaka University Hospital, Japan.
X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.
PMID: 1734865, UI: 92134262
Linkage analysis of spinal muscular atrophy.
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
Linkage data between four markers on chromosome 5 confirm and extend our previous studies that localized the mutation in spinal muscular atrophy to 5q11.2-q13.3. Localization of D5S6 by in situ hybridization refines the mapping of the defective gene to the region 5q12.2-q13. We also report the use of a highly informative PCR-based polymorphism with five alleles. This RFLP will be particularly useful for prenatal diagnosis where only old tissue samples from affected individuals are available. The high heterozygosity of this locus should also assist in identifying recombinants that will refine the genetic mapping of the mutation.
Grant support:
PMID: 1346777, UI: 92155724
Muscle Nerve 1991 Dec;14(12):1236-1241
Neuromuscular Unit, Tufts Medical School, Boston, Massachusetts.
We reviewed the role of electrodiagnostic testing in amyotrophic lateral sclerosis (ALS) in a large ALS clinic. Over 31 months, 133 patients with a clinical diagnosis of ALS were tested. In most, nerve conduction studies were normal, and needle electrode examination showed active denervation in the upper and lower limbs or the limbs and bulbar muscles (Lambert's criteria). However, 50 of 133 patients did not fulfill Lambert's criteria at presentation because of abnormal nerve conduction studies (11 patients), abnormal F-wave latencies (6 patients), or insufficiently distributed fibrillation potentials (40 patients). This study reveals that a large proportion of patients with a clinical diagnosis of ALS fail to have classical findings on initial electrodiagnostic studies, and reveals several caveats of electrodiagnostic testing in these patients: (1) Conduction studies may be unreliable in motor nerves with markedly low compound muscle action potential (CMAP) amplitudes. (2) Sensory nerve action potential (SNAP) amplitudes may be abnormal in a small percentage of otherwise typical ALS patients. However, better controls for elderly subjects are needed. (3) Needle electrode examination may not show widespread active denervation early in the disease. (4) Some patients may have a mild polyneuropathy. (5) The classic diagnostic criteria may need to be modified to allow earlier acceptance of many ALS patients into therapeutic trials.
PMID: 1766455, UI: 92114913
Nature 1991 Jul 4;352(6330):77-79
Neurology Department, University of Pennsylvania School of Medicine, Philadelphia 19104-6146.
X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.
PMID: 2062380, UI: 91287825
Neurology 1991 Jun;41(6):823-828
Department of Neurology, School of Medicine, University of California, San Francisco 94143-0114.
We describe four men from two kinships affected with X-linked recessive bulbospinal neuronopathy, and one sporadic case. All developed postural tremor, weakness, and fasciculations, with onset from age 25 to 39 years. Weakness began in the pelvic girdle or hands, with dysphagia or dysarthria occurring years later in two. Sensory symptoms were present in only one, who also had diabetes mellitus. In contrast, sural nerve action potentials were small or absent in all. Needle EMG showed widespread chronic partial denervation with reinnervation. The characteristic twitching of the chin produced by pursing of the lips consisted of repetitive or grouped motor unit discharges, rather than fasciculations. Broader awareness of the distinctive features of bulbospinal neuronopathy will probably increase the frequency of its recognition. Diagnosis is important for purposes of providing a prognosis for affected men and genetic counseling for affected families.
Comments:
PMID: 2046924, UI: 91261155
J Steroid Biochem Mol Biol 1991;40(1-3):349-352
Department of Biochemistry II, Erasmus University, Rotterdam, The Netherlands.
The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the corresponding gene has enabled us to study androgen receptors in subjects with the clinical manifestation of androgen insensitivity and in a human prostate carcinoma cell line (LNCaP). Using PCR amplification, subcloning and sequencing of exons 2-8, we identified a G----T mutation in the androgen receptor gene of a subject with the complete form of androgen insensitivity, which inactivates the splice donor site at the exon 4/intron 4 boundary. This mutation causes the activation of a cryptic splice donor site in exon 4, which results in the deletion of 41 amino acids from the steroid binding domain. In two other independently arising cases we identified two different nucleotide alterations in codon 686 (GAC; aspartic acid) located in exon 4. One mutation (G----C) results in an aspartic acid----histidine substitution (with negligible androgen binding), whereas the other mutation (G----A) leads to an aspartic acid----asparagine substitution (normal androgen binding, but a rapidly dissociating androgen receptor complex). Sequence analysis of the androgen receptor in human LNCaP-cells (lymph node carcinoma of the prostate) revealed a point mutation (A----G) in codon 868 in exon 8 resulting in the substitution of threonine by alanine. This mutation is the cause of the altered steroid binding specificity of the LNCaP-cell androgen receptor. The functional consequences of the observed mutations with respect to protein expression, specific ligand binding and transcriptional activation, were established after transient expression of the mutant receptors in COS and HeLa cells. These findings illustrate that functional errors in the human androgen receptor have an enormous impact on phenotype and fertility.
PMID: 1958538, UI: 92068833
Neuromuscul Disord 1991;1(2):83-85
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, U.K.
Spinal muscular atrophy (SMA) is inherited as an autosomal recessive disorder which presents as a severe, intermediate or mild condition. The disease selectively affects the alpha motor neuron but nothing is as yet known about the underlying biochemical defect. Recent genetic studies have mapped all three types of SMA to the same region of human chromosome 5 (5q11.2-q13.3) raising the possibility that the mutations may be allelic. Polymorphic DNA markers have been characterised which are suitable for prenatal diagnosis. This is the first step in the isolation of the mutant gene (or genes) involved in this disorder.
PMID: 1822785, UI: 92353691
J Med 1991;22(2):123-130
Third Department of Internal Medicine, Okayama University Medical School, Japan.
We describe a 72-year-old male with bulbospinal muscular atrophy (BSMA) who was being treated for diabetes mellitus and congestive heart failure due to an old myocardial infarction. Although BSMA is a rare form of X-linked spinal and bulbar muscular atrophy of late onset, this case is a sporadic case. We emphasize the importance of recognizing a sporadic case of BSMA.
PMID: 1895014, UI: 91373956
Brain 1990 Oct;113( Pt 5):1511-1525
Department of Clinical Neurological Sciences, University of Western Ontario, Victoria Hospital, London, Canada.
Modern techniques have defined the hereditary motor and sensory neuropathies (HMSN) as a genetically heterogeneous group of disorders. This includes a rare variant with X-linked dominant inheritance. We have traced this disorder through 6 generations of a large Canadian kindred; neurological and electrophysiological examinations were performed in 57 family members and nerve biopsies were studied in 2 affected males, early and late in the disease; 42/83 family members were affected. No male-to-male transmission was encountered in 19 sons of affected fathers, whereas all their daughters expressed the disease. Linkage was shown to the DNA loci DXYS1 Z max = 2.87 at theta max = 0.06 and to PGK1 Z max = 1.51 at theta max = 0 (Beckett et al., 1986). The typical clinical features are onset in early childhood, pes cavus, atrophy and weakness of peroneal muscles and intrinsic hand muscles, and sensory abnormalities. Males were severely affected, whereas females had mild or subclinical disease. Electrophysiological observations indicated a substantial loss of distal motor and sensory nerve fibres. Evoked compound muscle action potentials in extensor digitorum brevis were absent or severely reduced in 42% of cases and the peroneal motor nerve conduction velocity was mildly reduced to a mean 36.5 +/- 7.4 m.s-1. Sural sensory nerve action potentials were absent or severely reduced in 75% of those affected. Nerve biopsies showed loss of myelinated and unmyelinated nerve fibres, regenerative sprouting and secondary demyelination. The findings indicate that this distinct variant of HMSN is the result of primary axonal degeneration.
PMID: 2245309, UI: 91059187
Arch Neurol 1990 Oct;47(10):1117-1120
Department of Neurology, State University of New York, Buffalo.
Kennedy's syndrome, X-linked adult-onset bulbospinal muscular atrophy, has been described in over 30 families. The characteristic distribution of weakness creates a recognizable syndrome, augmented by frequent findings of testicular atrophy and gynecomastia. Type IV or type II hyperlipoproteinemia has been found in some families. We have studied another family with Kennedy's syndrome, this one with hypobetalipoproteinemia. The diversity of serum patterns suggests that lipoprotein abnormalities are not causally related to either the endocrinopathy or the spinal muscular atrophy. However, gene linkage studies indicate proximity of the gene for Kennedy's syndrome and the gene encoding the androgen receptor, which could explain the combination of a motor neuron disorder and the endocrine abnormalities.
Grant support:
PMID: 2222245, UI: 91024658
Rinsho Shinkeigaku 1990 Aug;30(8):828-834
[Article in Japanese]
Department of Neurology, Fujita Gakuen Health University, School of Medicine.
We analysed the patterns of skeletal muscular involvement in 18 patients with bulbar-spinal muscular atrophy (BSMA) of the Kennedy-Alter-Sung type by using the computed tomographic scanner. Fatty infiltrations were prominent in various skeletal muscles of extremities and trunk, and its degree was severe in the following numerical orders; the gluteal muscles, flexors of the thighs, flexors of the lower extremities, extensors and the adductors of the thighs, the paraspinal muscles, and extensors of the lower extremities. There was statistically significant correlation between fatty infiltrations in flexors of the lower extremities and duration of illness. And were noted findings that the skeletal muscle lesion progressed with the preserved fasciae and sectional areas, fatty infiltrations in the lower extremities were more conspicuous in flexors than in extensors, and compensatory hypertrophic muscles in the thigh were apparent in 50% of cases. In conclusions, the computed tomographic analyses on skeletal muscle of BSMA may be useful to detect distributions, progression of the muscle lesion, in addition to a profile of the myopathic alterations of the disease.
PMID: 2253416, UI: 91070855
Z Orthop Ihre Grenzgeb 1990 Mar;128(2):123-127
[Article in German]
Abt. Neuropadiatrie der Stadtischen Kinderklinik Esslingen.
Two sisters suffering from a hereditary motor-sensory neuropathy (HMSN) are described. A walking disturbance, deformations of foot, muscle atrophy, areflexia of the legs with disturbance of sensibility are detectable of them. Each of them, their motor nerve conduction velocity (NCV) of all extremities was slowed. The younger of the two sisters had graver symptoms and her sural nerve biopsy exhibited a reduced number of myelinated nerve fibres, some distinguished axon-calibre and onion bulb-formations. The relation of those findings to the classification of HMSN is demonstrated and the importance of NCV-measurement to clarification of walking disturbance is shown.
PMID: 2140641, UI: 90266618
Muscle Nerve 1989 Nov;12(11):875-882
Department of Neurology, University of Massachusetts Medical Center, Worcester 01655.
A case study is reported regarding a 32-year-old man with classic clinical and electrophysiologic features of hereditary motor and sensory neuropathy, type I (HMSN I), a slowly progressive autosomal dominant condition marked by slow motor and sensory velocities and generalized segmental demyelination. Another clinically similar autosomal dominant neuropathy (HMSN II) is distinguished from HMSN I by nearly normal nerve conduction velocity. Acquired demyelinating neuropathy may occasionally resemble HMSN I clinically, but the former demonstrates electrophysiologic features not seen in the latter such as conduction block, dispersed compound muscle action potentials, and differential slowing of conduction velocity. Neuropathologic studies of HMSN I suggest that both neuronal and Schwann cell distrubances play a role in pathogenesis.
Comments:
PMID: 2608082, UI: 90114301
Neurophysiol Clin 1989 May;19(2):163-170
[Article in French]
Service de neurologie A, Laboratoire de neuro-immunologie et neuropathologie, INSERM U 298, Angers, France.
Two new cases of X-chromosome linked bulbospinal muscular atrophy associated with gynecomastia (described by Kennedy in 1968) are reported. In one patient, an electrophysiological study and a muscle nerve biopsy were performed. Motor nerve conduction studies were normal but sensory action potentials were small or unrecordable in the absence of clinical sensory loss. Superficial peroneal nerve biopsy showed axonal lesions. These findings suggest that this disease is not purely due to degeneration of spinal motor neurons and is also associated with an axonopathy.
PMID: 2542754, UI: 89261589
Funct Neurol 1989 Apr;4(2):173-175
Institute of Neurology, University of Ancona, Italy.
Twenty subjects suffering from chronic renal failure and undergoing continual treatment by haemodialysis were examined, and the following values assessed: maximum conduction velocity of the sensory and motor fibres of the common peroneal nerve, the relative electromyographic parameters, and the sympathetic skin response at the level of the foot. The results obtained have shown that autonomic neuropathy involving the sympathetic sudomotor is less frequent than sensorimotor neuropathy. The autonomic failures are scanty in the mild forms of sensorimotor neuropathy, with minor latency in the onset of uremia.
PMID: 2737506, UI: 89290458
No To Shinkei 1989 Feb;41(2):143-148
[Article in Japanese]
Third Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
We reported a case with Kennedy-Alter-Sung syndrome (KAS) associated with bilateral external ophthalmoplegia. The patient had movement disturbance of bilateral infra-oblique muscles. The doll's eye phenomenon was not noted. It was suggested that the external ophthalmoplegia was due to the involvement of the oculomotor nucleus that innervated infra-oblique muscle. The serum levels of testosterone and gonadotropin were high, suggesting that the feminization of KAS patients was caused by androgen insensitivity. The feminization of KAS patients is similar to the incomplete form of testicular feminization syndrome except that they do not have feminization of genitals. Therefore, we proposed that abnormalities of androgen receptors might play a role in the pathogenesis of KAS. Fluoxymesterone therapy significantly improved the muscle weakness of the extremities of the patient, even though the therapeutic efficacy was shown temporarily. The therapeutic efficacy of fluoxymesterone for muscle weakness supports our hypothesis.
PMID: 2500144, UI: 89287155
Zh Nevropatol Psikhiatr 1989;89(12):39-44
[Article in Russian]
The authors describe a familial case of Kennedy's spinal amyotrophy. In three brothers of the R. family, the disease was marked by the appearance in the 4th-5th decade of life of myasthenia in the proximal parts of the limbs and of bulbar symptoms, which will run a slow-progressive course. Since the young age all the patients manifested gynecomastia. Besides, later one of the brothers developed scirrhus of the left mammary gland. Clinically, Kennedy's spinal amyotrophy in the R. family manifested itself by asymmetric distribution of myotrophies (more pronounced in the left limbs), bilateral Dupuytren's contractures in the hands. Apart from the signs of injuries to motoneurons of the anterior horns, electromyography and electroneuromyography have shown the peripheral nerves to be involved into the pathological process.
PMID: 2633568, UI: 90224409
J Neurol Sci 1988 Nov;87(2-3):141-152
Department of Neurology, Tokyo Metropolitan Neurological Hospital, Japan.
Autopsy cases of two brothers with bulbo-spinal muscular atrophy associated with gynecomastia, testicular atrophy and sensory neuropathy are reported. The disease started with finger tremor, proximal muscle weakness and facial muscle twitching at the second and fourth decades, accompanied by bulbar signs and glove-stocking type sensory disturbance. Systemic neurogenic patterns and diminished sensory nerve action potential amplitudes were recorded by electrophysiological studies. A marked loss of myelinated fibers was noticed upon sural nerve biopsy. Gonadal hormone values were normal, except for elevated urinary estrogen. Postmortem examinations revealed a remarkable degeneration of the facial and hypoglossal nuclei, and the spinal cord motoneurons. The skeletal muscles and the tongue showed neurogenic muscular atrophy with fatty replacement. Testicular atrophy was prominent showing hyalinized seminiferous tubuli with nodular and diffuse Leydig cell hyperplasia, containing estrogen immunoreactive substance. These clinical and histological features seemed to be highly compatible with those of Kennedy-Alter-Sung type bulbo-spinal muscular atrophy. The involvement of sensory peripheral nerves, however, was a distinct feature of this family.
PMID: 3210030, UI: 89094398
Rev Neurol (Paris) 1988;144(11):756-758
[Article in French]
C.H.U. Timone, Marseille.
Kennedy's syndrome is usually classified among the progressive spinal amyotrophies. Scarce reports suggest the involvement of the peripheral nerves. Five cases are reported here with a decrease of the sensory potential amplitude. A pathological study in 4 of these cases showed lesions of the sensory nerve. The notion of neuronopathy is discussed because it underlines the physiological unity of the cellular body and of the axon and the difficulty to separate the reciprocal damage in certain pathological cases. It would be excessive to equate clinical and experimental cases in which the onset of the disease involves either the cellular body or the axon.
PMID: 3231965, UI: 89161687
Clin Genet 1987 Dec;32(6):414-415
Publication Types:
PMID: 3436091, UI: 88136277
Clin Neuropathol 1987 Mar;6(2):55-60
A 66-year-old male with no family history of neurological disease developed symmetrical paraesthesia, numbness and flaccid weakness of the hands and feet. Both the weakness and sensory loss became progressively more severe, and spread to involve the forearms and lower legs. Limb muscle wasting and tongue fasciculation only became apparent late in the disease course, and death eventually occurred from respiratory failure eight years after the onset of symptoms. Postmortem examination revealed most of the typical histological features of motor neuron disease, but in addition there was degeneration of the spinocerebellar tracts and spinal cord posterior columns, with degeneration and loss of their associated neuronal perikarya in Clarke's nuclei and dorsal root ganglia. The clinical and pathological features of this case suggest that it is a non-familial but atypical form of motor neuron disease, and support the concept that this disease represents part of a spectrum of neuronal degenerative processes rather than a circumscribed disorder limited to motor neurons.
PMID: 3474092, UI: 87245142
Med Clin North Am 1986 Nov;70(6):1333-1347
EMG and conduction studies provide the physician with a precise means of defining the multiple diseases affecting the peripheral motor-sensory unit. These studies frequently provide clues that may be useful in arriving at the appropriate therapeutic decisions and in determining prognosis. Normal results may also support a suspected clinical diagnosis of inorganic illness, providing no evidence of central nervous system disease can be defined. Like any other test, however, results of EMG may be false-negative in bona fide neuromuscular disorders. This is particularly true early in a disease process; in neuropathies restricted primarily to small, unmyelinated nerve fibers; and in certain of the less virulent diseases of muscle and muscle energy metabolism.
PMID: 3784694, UI: 87062904
Muscle Nerve 1986 Jan;9(1):64-68
We report a patient with progressive muscle weakness, areflexia, and no sensory loss. Electromyography revealed normal sensory nerve conductions, mild slowing of motor nerve conduction velocities, low amplitude compound muscle action potentials, a neuromuscular transmission defect characterized by prominent facilitation, and diffuse fibrillation potentials. Muscle biopsies showed acute denervation atrophy, and at autopsy, there was anterior horn cell loss and gliosis in the spinal cord. The findings suggest the coexistence of a motor neuropathy and a facilitating myasthenic syndrome.
PMID: 3005856, UI: 86146726
Rev Neurol (Paris) 1984;140(12):720-727
[Article in French]
An X-linked spinal muscular atrophy is reported in one family. Four of the five patients were examined. In three, electromyography, conduction nerve velocities and muscle biopsy were consistent with anterior horn cell disease. Similar families in the literature were reviewed and characteristic data were: 1) adult-onset, 2) proximal, bulbar and facial involvement, 3) prominent perioral fasciculations, 4) frequent association of cramps, tremor and sexual dysfunction (hypogonadism and gynecomastia), 5) very slow progression and favorable prognosis. These characteristics define, among the spinal muscular atrophies, a distinct entity named by several authors Kennedy's disease.
PMID: 6543025, UI: 85114815
Eur Neurol 1981;20(6):485-488
X-linked spinal and bulbar muscular atrophy of late onset is a rare variety of motor neuron disease. In this report a Greek family with 2 affected brothers is described. It is interesting that all Greek cases of this disease originate from a small group of Greek islands. Transient fatigue is an additional feature of the disease which is manifested sometimes before other symptoms are apparent. The progression of the disease appears to be faster than in spinal muscular atrophy of Wohlfart-Kugelberg-Welander. Regarding the name of this disorder, we propose the descriptive term, 'X-linked spinal and bulbar atrophy of late onset' or 'Kennedy-Stefanis disease.
PMID: 7308249, UI: 82072829
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